Despite the dramatic reduction in HIV-associated morbidity and mortality accompanying the introduction of highly active antiretroviral therapy (HAART), there has emerged a concomitant recognition of important metabolic complications involving abnormalities of fat distribution, carbohydrate and lipid metabolism, and bone mineralization. Given the potential implications of these findings for risk of cardiovascular disease and osteoporotic fractures, there exists a need to better characterize the epidemiology and underlying mechanisms of these syndromes and to evaluate potential targeted interventions. The current application expands upon the investigators' previous studies in this area and will address many of these issues through three specific aims: 1) To test the hypotheses that the thiazolidinediones improve glucose homeostasis and increase subcutaneous adipose tissue in patients with HIV-associated lipoatrophy, they will measure insulin sensitivity, glucose tolerance, hepatic glucose production, and total, visceral and subcutaneous fat in patients with HIV-associated lipoatrophy before and after six months of rosiglitazone therapy. Associated changes in lipid metabolism will be assessed by measuring lipid and lipoprotein levels, fat clearance, whole-body lipolysis, and hepatic de novo lipogenesis. 2) To test the hypothesis that low-dose growth hormone is effective in the treatment of HIV-associated fat accumulation, they will measure total, trunk, and visceral fat before and after six months of growth hormone at 1 mg/day. To determine the effects of growth hormone on carbohydrate and lipid metabolism, they will measure insulin sensitivity, glucose tolerance, hepatic glucose production, lipid and lipoprotein levels, fat clearance, whole body lipolysis, and hepatic de novo lipogenesis before and during growth hormone treatment. 3) To test the hypothesis that treatment with HAART is associated with lower bone mineral density (BMD) in HIV-infected patients and to identify independent patient- and disease-related predictors of low bone density, they will perform cross-sectional and longitudinal measurements of BMD, biochemical markers of bone turnover, and related metabolic factors in patients about to initiate to HAART and in patients who are stable on HAART with effective viral suppression. A clearer understanding of these metabolic disorders and potential targeted interventions may impact significantly on the therapeutic management of HIV infection. INVESTIGATORS:Dr. Joan Lo received the M.S. degree in biochemistry at UCLA and the M.D. degree from Harvard Medical School in 1993. She was a resident in Internal Medicine at Brigham and Women's Hospital from 1993 to 1996. In 1996, she became a fellow in endocrinology and metabolism at the UCSF focusing her studies under the mentorship of Dr. Morris Schambelan, Chief of Endocrinology and Program Director of the GCRC and working also with Dr. Kathleen Mulligan at the San Francisco General Hospital GCRC. Her initial studies focused on altered fat distribution in HIV infected patients and she received a CAP award to extend these studies in an intensive clinical metabolic investigation using glucose clamp methodology, carbohydrate fat tolerance and body composition measurements. She has eight publications as a CAP recipient; three as first author (although two are reviews). During the first couple of years of her CAP award, she initiated pilot studies in the use of growth hormone for excess visceral adiposity in HIV infected patients with fat accumulation; this was the first study to carefully evaluate the effects of growth hormone on both insulin action and glucose metabolism and on hepatic carbohydrate and liver metabolism in this population. She has also published a review of reproductive function of HIV infection and has collaborated on very important and novel studies of the effects of protease inhibitors on insulin resistant and HIV negative individuals. She has had very good productivity in her initial years as a CAP recipient; the current proposal seeks to extend these studies both in fat accumulation and fat loss in HIV infected patients as well as initiating bone studies. Her support letters are very strong. She clearly is an excellent candidate. It is of note that her letter from Dr. Schambelan suggests that she is likely to receive a faculty appointment at San Francisco General Hospital in the Division of Endocrinology, focusing particularly on bone abnormalities since there is currently no member of the faculty who studies bone. Her sponsor/mentor is Dr. Morris Schambelan. He is Professor of Medicine at UCSF and the Program Director of the GCRC. Dr. Schambelan is a very well-established investigator in endocrinology who for the last 10-12 years has concentrated on the pathogenesis and treatment of metabolic and endocrine disturbances in patients with HIV and AIDS and his group at San Francisco General Hospital is widely recognized as one of the world leaders of investigation in this field. His group has made major contributions to our understanding of these abnormalities and potential therapies for HIV infected patients. In addition to being Program Director for the GCRC, Dr. Schambelan is currently a principal investigator on three NIH R01s and co-investigator on a fourth. It is interesting to note that one of the R01s overlaps in Aims 1 and 2 for Dr. Lo's proposals; however, Dr. Schambelan makes it clear that his grant will make available supplies and other costs that could not be covered in the CAP award. Dr. Schambelan is an outstanding mentor. He has a clear and strong record in training young investigators and his record already with Dr. Lo is superb. In addition, Dr. Dolores Shoback, Professor of Medicine at UCSF, would provide mentorship for the studies in bone metabolism. Dr. Shoback is well qualified to provide insight and support for these studies. However, her involvement in the design of the proposed studies is unclear, and her expertise in the epidemiology of osteoporosis is quite limited.